≪ View Page

Differences

This shows you the differences between two versions of the page.

Link to this comparison view

Both sides previous revisionPrevious revision
Next revision		Previous revision
beta_blocker_toxicity [2025/02/21 00:21] – jkohtsbeta_blocker_toxicity [2025/04/16 04:05] (current) – [10.1 Supportive] jkohts
Line 9: Line 9:
  
 There are a number of ways to classify β-blockers. A simple functional classification for __therapeutic__ use is described in the table below [(31178382>[[https://pubmed.ncbi.nlm.nih.gov/31178382/|PMID: 31178382]]. Oliver E, Mayor F Jr, D'Ocon P. Beta-blockers: Historical Perspective and Mechanisms of Action. Rev Esp Cardiol (Engl Ed). 2019;72(10):853-862. doi:10.1016/j.rec.2019.04.006)]. Importantly, receptor selectivity is lost in overdose. There are a number of ways to classify β-blockers. A simple functional classification for __therapeutic__ use is described in the table below [(31178382>[[https://pubmed.ncbi.nlm.nih.gov/31178382/|PMID: 31178382]]. Oliver E, Mayor F Jr, D'Ocon P. Beta-blockers: Historical Perspective and Mechanisms of Action. Rev Esp Cardiol (Engl Ed). 2019;72(10):853-862. doi:10.1016/j.rec.2019.04.006)]. Importantly, receptor selectivity is lost in overdose.
 +
  
 <WRAP group><WRAP column> <WRAP group><WRAP column>
Line 17: Line 18:
  
 </WRAP></WRAP> </WRAP></WRAP>
 +===== - Mechanism of Toxicity =====
  
-===== - Mechanism of toxicity ===== +==== - β-Adrenergic Antagonism ====
- +
-==== - β-adrenergic antagonism ====+
  
 Excess competitive inhibition at β-adrenergic receptors primarily cause bradycardia and hypotension for all drugs in this class. There is a loss of receptor selectivity in overdose. Excess competitive inhibition at β-adrenergic receptors primarily cause bradycardia and hypotension for all drugs in this class. There is a loss of receptor selectivity in overdose.
  
-=== - β1-adrenergic antagonism ===+=== β1-Adrenergic Antagonism ===
 β1-receptors are found primarily in cardiac tissue, and when stimulated results in increased chronotropy, inotropy, automaticity, and dromotropy. β-antagonists depress these effects, and toxicity primarily manifests as suppression of cardiac functions with bradycardia, hypotension, and cardiogenic shock. β1-receptors are found primarily in cardiac tissue, and when stimulated results in increased chronotropy, inotropy, automaticity, and dromotropy. β-antagonists depress these effects, and toxicity primarily manifests as suppression of cardiac functions with bradycardia, hypotension, and cardiogenic shock.
  
-=== - β2-adrenergic antagonism ===+=== β2-Adrenergic Antagonism ===
 β2-receptors are found in peripheral smooth muscle vasculature, airway smooth muscle, liver, GI tract, pancreas, uterus, and to a lesser extent cardiac tissue. When stimulated, vasodilation and bronchodilation occur. The toxic effects of β-antagonists can manifest as bronchospasm in susceptible individuals. β2-receptors are found in peripheral smooth muscle vasculature, airway smooth muscle, liver, GI tract, pancreas, uterus, and to a lesser extent cardiac tissue. When stimulated, vasodilation and bronchodilation occur. The toxic effects of β-antagonists can manifest as bronchospasm in susceptible individuals.
  
 β-blockers may also cause hypoglycemia by inhibition of hepatic glycogenolysis and pancreatic glucagon release. Counter-regulation by adrenaline is also diminished by β-blockade, further compounding hypoglycemia. β-blockers may also cause hypoglycemia by inhibition of hepatic glycogenolysis and pancreatic glucagon release. Counter-regulation by adrenaline is also diminished by β-blockade, further compounding hypoglycemia.
  
-==== - Other features of β-blockers ====+==== - Other Features of β-Blockers ====
  
 Individual drugs in this class differ based on their unique pharmacological properties, which include: Individual drugs in this class differ based on their unique pharmacological properties, which include:
Line 44: Line 44:
   * Renal/hepatic clearance   * Renal/hepatic clearance
  
-=== - Cardioselectivity (β1-selectivity) ===+=== Cardioselectivity (β1-Selectivity) ===
 While β1-selectivity can influence adverse effects in therapeutic use, it becomes less relevant in overdose situations because selectivity is lost at high drug concentrations. While β1-selectivity can influence adverse effects in therapeutic use, it becomes less relevant in overdose situations because selectivity is lost at high drug concentrations.
  
-=== - Intrinsic sympathomimetic activity (ISA) ===+=== Intrinsic Sympathomimetic Activity (ISA) ===
 Some β-blockers have ISA due to partial β agonism and may result in tachycardia and hypertension. This partial agonist effect rarely leads to significant problems and probably protects to some extent from the more serious class I and III antiarrhythmic effects. Drugs with ISA include acebutolol, pindolol, labetalol, and celiprolol. Some β-blockers have ISA due to partial β agonism and may result in tachycardia and hypertension. This partial agonist effect rarely leads to significant problems and probably protects to some extent from the more serious class I and III antiarrhythmic effects. Drugs with ISA include acebutolol, pindolol, labetalol, and celiprolol.
  
-=== - Membrane-stabilizing activity / class I antiarrhythmic effects ===+=== Membrane-Stabilizing Activity / Class I Antiarrhythmic Effects ===
 The membrane-stabilizing activity of some β-blockers is due to the inhibition of fast Na+ channels (class I anti-arrhythmic activity). These effects usually only occur at high drug concentrations. Propranolol has the most membrane-stabilizing activity of the β-blockers and can result in impaired AV conduction, widened QRS interval, ventricular tachyarrhythmias, coma, and seizures. The membrane-stabilizing activity of some β-blockers is due to the inhibition of fast Na+ channels (class I anti-arrhythmic activity). These effects usually only occur at high drug concentrations. Propranolol has the most membrane-stabilizing activity of the β-blockers and can result in impaired AV conduction, widened QRS interval, ventricular tachyarrhythmias, coma, and seizures.
  
-=== - K+ channel blockade / class III antiarrhythmic effects ===+=== K+ Channel Blockade / Class III Antiarrhythmic Effects ===
 Some β-blockers block the delayed rectifier outward K+ channel which is responsible for cell repolarization. This prolongs the action potential duration and prolongs the QT interval, which can predispose to arrhythmias. Examples of these β-blockers include sotalol and acebutolol. Some β-blockers block the delayed rectifier outward K+ channel which is responsible for cell repolarization. This prolongs the action potential duration and prolongs the QT interval, which can predispose to arrhythmias. Examples of these β-blockers include sotalol and acebutolol.
  
-=== - Vasodilatory activity ===+=== Vasodilatory Activity ===
 The vasodilatory activity of certain β-blockers can theoretically enhance the hypotensive effects in cases of β-blocker overdose. The vasodilatory activity of certain β-blockers can theoretically enhance the hypotensive effects in cases of β-blocker overdose.
  
-=== - Lipid solubility ===+=== Lipid Solubility ===
 Only lipid soluble drugs will lead to direct CNS effects as they are able to penetrate the blood brain barrier, though CNS symptoms may occur secondary to cardiac effects and decreased cerebral perfusion. Lipid solubility alone will not lead to CNS effects and they may relate to Na+ channel blocking effects as they are particularly common with propranolol. Only lipid soluble drugs will lead to direct CNS effects as they are able to penetrate the blood brain barrier, though CNS symptoms may occur secondary to cardiac effects and decreased cerebral perfusion. Lipid solubility alone will not lead to CNS effects and they may relate to Na+ channel blocking effects as they are particularly common with propranolol.
  
-=== - Renal/hepatic clearance ===+=== Renal/Hepatic Clearance ===
 This is occasionally important in therapeutics but is largely irrelevant in overdose. This is occasionally important in therapeutics but is largely irrelevant in overdose.
  
-===== - Risk assessment =====+===== - Risk Assessment =====
  
 The toxic dose of β-blockers is variable and depends on individual susceptibility and drug type. Factors associated with increased risk of toxicity include: The toxic dose of β-blockers is variable and depends on individual susceptibility and drug type. Factors associated with increased risk of toxicity include:
Line 78: Line 78:
  
  
-===== - Pharmacokinetics and toxicokinetics =====+===== - Kinetics in Overdose =====
  
 ==== - Absorption ==== ==== - Absorption ====
Line 96: Line 96:
 The more water-soluble β-blockers (atenolol, sotalol) are primarily excreted unchanged by the kidneys. The more lipid-soluble β-blockers undergo extensive hepatic metabolism, and their metabolites are excreted via the urine or bile. The more water-soluble β-blockers (atenolol, sotalol) are primarily excreted unchanged by the kidneys. The more lipid-soluble β-blockers undergo extensive hepatic metabolism, and their metabolites are excreted via the urine or bile.
  
-===== - Clinical effects =====+===== - Clinical Effects =====
  
 The principal clinical effects of β-blocker toxicity are hypotension and bradycardia. The principal clinical effects of β-blocker toxicity are hypotension and bradycardia.
  
-==== - Cardiovascular effects ====+__**CVS:**__ 
 +  * **Bradydysrhythmias:** varying degrees (sinus, 1°-3° heart block, junctional/ventricular bradycardia, asystole). Vagal stimuli may precipitate cardiac arrest. QRS and QT prolongation are a measure of severity. 
 +  * **Pump failure** / direct myocardial depression 
 +  * **Hypotension:** due to combination of bradycardia and pump failure
  
-The cardiovascular manifestations of β-antagonist poisoning typically are bradydysrhythmias, cardiac conduction defects, hypotension, and circulatory shock.+__**CNS:**__ 
 +  * **CNS depression:** drowsiness commonly due to cardiovascular depression and decreased cerebral perfusion, and may respond to correction of hypotension. 
 +  * **Seizures:** lipophilic β-blockers (e.g. propranolol) disproportionately implicated. Risk factors for seizures in propranolol overdose include ingestion of > 2 g of propranolol and QRS width >100 ms [(8667464>[[https://pubmed.ncbi.nlm.nih.gov/8667464/|PMID: 8667464]]. Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-278. doi:10.3109/15563659609013789)].
  
-=== - Bradyarrhythmias and cardiac conduction defects === +__**Resp:**__ 
-Varying degrees of bradyarrhythmia may occur (sinus bradycardia, 1st to 3rd degree heart block, junctional or ventricular bradycardia, or asystole) and deterioration may occur rapidly and without warning. Vagal stimuli (gastric lavage, emesis, intubation) and seizures are precipitants for cardiac arrest. Atropine pretreatment should be used prior to any intervention that could enhance vagal tone. Other ECG changes including QRS and QT prolongation occur and are a measure of severity.+  * **Bronchospasm:** due to β2 antagonism particularly in individuals with underlying reactive airway disease.
  
-=== - Pump failure === +__**Metabolic:**__ 
-Direct myocardial depression due to the negative inotropic effects of β-blockers can complicate circulatory shock.+  * **Hypoglycemia:** β-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.
  
-=== - Hypotension === 
-Hypotension occurs due to a combination of bradycardia (with or without heart block) and direct myocardial depression. Toxicity develops over the first few hours. Intractable hypotension with extreme bradycardia and/or asystole is the usual mode of death. 
- 
-==== - Neurological effects ==== 
- 
-The two primary neurologic manifestations of β-blocker toxicity are CNS depression and seizures. 
- 
-=== - CNS depression === 
-Drowsiness is commonly due to cardiovascular depression and decreased cerebral perfusion, and may respond to correction of hypotension. 
- 
-=== - Seizures === 
-Seizures are primarily linked to overdoses of the lipophilic β-blockers with propranolol being disproportionately implicated. Risk factors for seizures in propranolol overdose include ingestion of > 2 g of propranolol and QRS width >100 ms [(8667464>[[https://pubmed.ncbi.nlm.nih.gov/8667464/|PMID: 8667464]]. Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-278. doi:10.3109/15563659609013789)]. 
- 
-==== - Respiratory effects ==== 
- 
-=== - Bronchospasm === 
-β-blocker overdose can result in bronchospasm as a result of β2 antagonism, particularly in individuals with underlying reactive airway disease. 
- 
-==== - Metabolic effects ==== 
- 
-=== - Hypoglycemia === 
-β-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis. 
  
 ===== - Investigations ===== ===== - Investigations =====
  
-==== - Lab tests ====+==== - Lab Tests ====
  
-=== - Blood glucose level ===+=== Blood Glucose Level ===
  
 β-blockers can cause hypoglycemia in overdose. β-blockers can cause hypoglycemia in overdose.
  
-=== - Serum biochemistry and blood gas ===+=== Serum Biochemistry and Blood Gas ===
 A basic biochemistry panel is used to assess for electrolyte derangements and renal function. A basic biochemistry panel is used to assess for electrolyte derangements and renal function.
  
-==== - Other tests ====+==== - Other Tests ====
  
-=== - ECG ===+=== ECG ===
 Serial 12-lead ECGs with continuous cardiac monitoring is used to identify signs of cardiotoxicity. These include: Serial 12-lead ECGs with continuous cardiac monitoring is used to identify signs of cardiotoxicity. These include:
  
Line 154: Line 137:
   * QRS widening, large terminal R wave in aVR (Na+ channel blockade)   * QRS widening, large terminal R wave in aVR (Na+ channel blockade)
  
-=== - Echocardiography ===+=== Echocardiography ===
 Cardiac POCUS or comprehensive TTE are used to diagnose and categorize the degree of myocardial dysfunction. This will guide cardiovascular therapies. Cardiac POCUS or comprehensive TTE are used to diagnose and categorize the degree of myocardial dysfunction. This will guide cardiovascular therapies.
  
-===== - Differential diagnosis =====+===== - Differential Diagnosis =====
  
 There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia. Correct diagnosis is important as these drugs have different specific treatments. There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia. Correct diagnosis is important as these drugs have different specific treatments.
Line 164: Line 147:
   * Calcium channel blocker toxicity causes bradycardia, hypotension, and __hyperglycemia__.   * Calcium channel blocker toxicity causes bradycardia, hypotension, and __hyperglycemia__.
  
-===== - Differences in toxicity within this drug class =====+===== - Differences in Toxicity Within This Drug Class =====
  
 ==== - Propranolol ==== ==== - Propranolol ====
Line 172: Line 155:
 Sotalol may frequently cause significant QT prolongation and torsade de pointes (occasionally reported with propranolol) as well as the usual manifestations of beta-blockade. Other factors relate to its intrinsic sympathomimetic (partial agonist) activity and lipid solubility (resulting in CNS effects). Sotalol may frequently cause significant QT prolongation and torsade de pointes (occasionally reported with propranolol) as well as the usual manifestations of beta-blockade. Other factors relate to its intrinsic sympathomimetic (partial agonist) activity and lipid solubility (resulting in CNS effects).
  
-===== - Management =====+===== - Treatment =====
  
-==== - Airway and Breathing ====+==== - Supportive ==== 
 + 
 +=== Airway and Breathing ===
 Invasive mechanical ventilation is indicated in refractory cardiovascular instability or reduced level of consciousness compromising airway and breathing. Administer atropine before intubation to block the vagal response to intubation, except in cases of cardiac arrest. Invasive mechanical ventilation is indicated in refractory cardiovascular instability or reduced level of consciousness compromising airway and breathing. Administer atropine before intubation to block the vagal response to intubation, except in cases of cardiac arrest.
  
-==== - Circulation ==== +=== Circulation === 
-Continuous ECG monitoring with serial 12-lead ECGs are indicated for all except minor β-blocker poisonings. Echocardiography is recommended to characterize the relative contributions of negative inotropy and vasodilation to the hypotension, and thus guide choice of treatment.+Continuous ECG monitoring with serial 12-lead ECGs are indicated for all except minor β-blocker poisonings. Echocardiography is recommended to characterize the relative contributions of negative inotropy and vasodilation to the hypotension, and thus guide choice of treatment. There are a number of drugs that will antagonize some of the cardiac effects of beta-blockers. All these treatments may be used simultaneously if required.
  
-=== - Hypotension === +  * **Hypotension:** IV fluid resuscitation (with normal saline or balanced crystalloid) should be initiated as first line management of hypotension. 
-IV fluid resuscitation (with normal saline or balanced crystalloid) should be initiated as first line management of hypotension. +  * **Bradycardia:** for bradycardia associated with hypotension, treat initially with [[treatment_atropine|atropine]] boluses. If bradycardia persists, consider infusion of [[treatment_adrenaline|adrenaline]] or isoprenaline. 
- +  * **Cardiogenic shock:** β-blockers can result in impaired myocardial contractility. In these cases, initiate an adrenaline infusion ± HIET.
-=== - Bradycardia === +
-For bradycardia associated with hypotension, treat initially with atropine boluses. If bradycardia persists, consider infusion of adrenaline or isoprenaline. +
- +
-=== - Cardiogenic shock === +
-β-blockers can result in impaired myocardial contractility. In these cases, initiate an adrenaline infusion ± HIET. +
- +
- +
-==== - Treatment ==== +
- +
-There are a number of drugs that will antagonize some of the cardiac effects of beta-blockers. All these treatments may be used simultaneously if required. +
- +
-  * Atropine +
-  * Glucagon +
-  * Isoprenaline +
-  * Dextrose & Insulin +
- +
-=== - Atropine === +
-This should be tried in all patients with bradycardia. It should be given prior to intubation, or any other procedure that might increase vagal tone and in patients who are nauseated or vomiting. +
- +
-=== - Isoprenaline == +
-Isoprenaline is a non-selective competitive β-agonist. Doses should also be titrated against cardiac parameters and the dose required may be ten or twenty fold larger than normally used. As both the agonist and antagonist are competing for the same receptors, much larger doses are needed to reach the same level of receptor occupancy. Dose requirements will fall rapidly as the β-blocking drug is metabolised. +
- +
-=== - HIET === +
-Patients who require inotropics support should be commenced on Dextrose & Insulin. This should be implemented in patients not responding to isoprenaline.+
  
 +=== Treatment of Specific Complications ===
 +  * **Seizures:** Glucose should be only given if hypoglycemic. Otherwise, they should be treated conventionally with benzodiazepines (eg diazepam) and a status epilepticus protocol.
 +  * **Arrhythmias:** Ventricular tachycardia (polymorphic VT, torsades de pointes) may occur with sotalol. Conventional treatment is with magnesium, isoprenaline, or cardiac pacing. Magnesium has calcium channel blocking effects and may further impair cardiac conduction and contractility, thus should be used with great caution. Isoprenaline or cardiac pacing may be used to achieve a heart rate of 100-120 bpm, to reduce the QT interval and thus the risk of torsades de pointes.
  
  
Line 216: Line 180:
 **Whole bowel irrigation** may be considered in patients who have ingested sustained-release preparations. **Whole bowel irrigation** may be considered in patients who have ingested sustained-release preparations.
  
-==== - Enhanced elimination ====+==== - Enhanced Elimination ====
  
 The drugs that are water soluble are predominantly renally cleared, namely sotalol and atenolol. Among these drugs, sotalol has significant 'antiarrhythmic' effects (via K+ channel blockade) and frequently causes life-threatening poisoning. The drugs that are water soluble are predominantly renally cleared, namely sotalol and atenolol. Among these drugs, sotalol has significant 'antiarrhythmic' effects (via K+ channel blockade) and frequently causes life-threatening poisoning.
Line 226: Line 190:
   * __Refractory__   cardiotoxic effects (bradycardia, hypotension, recurrent polymorphic VT)   * __Refractory__   cardiotoxic effects (bradycardia, hypotension, recurrent polymorphic VT)
  
 +==== - Antidote ====
 +There are no specific antidotes for β-blocker toxicity.
  
- +===== - Observation/Disposition =====
-==== - Treatment of specific complications ==== +
- +
-=== - Seizures === +
-Glucose should be only given if hypoglycemic. Otherwise, they should be treated conventionally with benzodiazepines (eg diazepam) and a status epilepticus protocol. +
- +
-=== - Arrhythmias === +
-Ventricular tachycardia (polymorphic VT, torsades de pointes) may occur with sotalol. Conventional treatment is with magnesium, isoprenaline, or cardiac pacing. Magnesium has calcium channel blocking effects and may further impair cardiac conduction and contractility, thus should be used with great caution. Isoprenaline or cardiac pacing may be used to achieve a heart rate of 100-120 bpm, to reduce the QT interval and thus the risk of torsades de pointes. +
- +
-==== - Observation/disposition ====+
 Admit all patients with symptomatic β-blocker toxicity, particularly those with: Admit all patients with symptomatic β-blocker toxicity, particularly those with:
   * Large ingestions   * Large ingestions
Line 252: Line 209:
 ===== - References ===== ===== - References =====
  
-Useful general references:+Further Reading:
  
   * [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7595901|Lip GY, Ferner RE.]] Poisoning with anti-hypertensive drugs: beta-adrenoceptor blocker drugs. J Hum Hypertens 1995; 9(4):213-221.   * [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7595901|Lip GY, Ferner RE.]] Poisoning with anti-hypertensive drugs: beta-adrenoceptor blocker drugs. J Hum Hypertens 1995; 9(4):213-221.